Carrier protein-monensin conjugates: enhancement of immunotoxin cytotoxicity and potential in tumor treatment.
We have investigated the potentiation of transferrin [Tfn]-toxin [Tfn-ricin toxin A chain (RTA) and Tfn-So6 saporin toxin] and monoclonal antibody-RTA conjugates by monensin (Mo) and by a human serum albumin (HSA)-monensin conjugate in vitro. The in vivo survival and in vitro and in vivo toxicity of HSA-Mo were also studied; monensin was chemically linked to HSA carrier protein via a disulfide bridge. HSA-Mo was 2-13-fold less toxic than Mo for cells in vitro. HSA-Mo was active in the same concentration range as Mo in potentiating mAb-RTA and Tfn-toxin conjugates reactive with Tfn receptors expressed by different cell lines in monolayer cell cultures. Multicell tumor spheroid cultures were used to investigate the target cell killing effect of cytotoxic conjugates and HSA-Mo in three-dimensional structures mimicking the properties of nonvascularized micrometastases. Spheroids 300-400 microns were as sensitive to Tfn-RTA and HSA-Mo in combination as monolayer cells. After 24 h incubation at 37 degrees C in human serum about 2% HSA-Mo molecules remained available for immunotoxin potentiation and about 10% after 24 h incubation in human cerebrospinal fluid. BALB/c mice tolerated injections of 2 mg/kg HSA-Mo i.v. and of 16 mg/kg i.p. The HSA-Mo half-life in the serum of BALB/c mice was 0.5 h. Following i.v. injection about 0.5% of the initial HSA-Mo persisted in the circulation at 24 h.
Colombatti
M
M
Istituto di Scienze Immunologiche, University of Verona, Italy.
Dell'Arciprete
L
L
Chignola
R
R
Tridente
G
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D000922:Immunotoxins / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007700:Kinetics; D008985:Monensin / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D012709:Serum Albumin / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D012709:Serum Albumin; D008985:Monensin